Heterocyclic amino-oxazolines



United States Patent O 3,511,851 HETEROCYCLIC AMINO-OXAZOLINES GeorgeLevitt, Wilmington, Del., assignor to E. I. du

Pont de Nemours and Company, Wilmington, Del., a

corporation of Delaware No Drawing. Filed June 12, 1967, Ser. No.646,153

Int. Cl. C07d 85/36 US. Cl. 260-307 11 Claims ABSTRACT OF THE DISCLOSUREAmino-oxazolines useful as central nervous system depressants having theformula:

wherein X is oxygen, sulfur or methylamino;

R is hydrogen or alkyl;

R' is hydrogen, alkyl, alkoXy, alkylthio,

dimethylamino, fluorine, chlorine or bromine;

R" is hydrogen or alkyl;

R is hydrogen or alkyl.

Typical is 2-(8-thiochromanylamino)-2-oxazoline useful as a centralnervous system depressant.

BACKGROUND OF THE INVENTION Patented May 12, 1970 "Ice SUMMARY ,OF THEINVENTION This invention relates to amino-oxazolines. More specificallythis invention refers to compounds of the formula:

X is oxygen, sulfur or methylamino;

R is hydrogen or alkyl of 1 through 4 carbon atoms;

R is hydrogen, alkyl of 1 through 4 carbon atoms, alkoxy of 1 through 4carbon atoms, alkylthio of 1 through 4 carbon atoms, dimethylamino,fluorine, chlorine, or bromine;

R" is hydrogen or alkyl of 1 through 4 carbon atoms;

R' is hydrogen or alkyl of 1 through 4 carbon atoms.

Preferred because of outstanding central nervous system depressantactivity are those compounds in Formulas 1, 2, 3 and 4 in which X isoxygen or sulfur, R, R" and R' are hydrogen and R is alkyl, alkoxy orhydrogen.

UTILITY The compounds of Formulas 1, 2, 3, and 4 above exhibitpharmaceutical properties including central nervous system depressantactivity.

Preferred compounds because of high therapeutic ratios at low rates ofuse are:

2- 8-thiochromanylamino -2-oxazoline,

2- 8-methy1-5-thiochromanylamino) -2-oxazoline,

2- S-chromanylamino -2-oxazoline,

2- 8-isothiochromanylamino -2-oxazoline,

2-(8-methyl-5-chromanylamino)-2-oxazo1ine,

2- 8-isochromanylamino 2-oxazoline,

2- 8-methyl-5-isothiochromanylamino -2-oxazoline,

2- S-thiochromanylamino -2-oxazoline,

2-( 1,2,3,4-tetrahydro-1-methyI-S-quinolinylamino) -2- oxazoline,

2- 8-methoxy-5-thiochromanylamino) -2-oxazoline.

PREPARATION The compounds of Formulas 1, 2, 3, and 4 above aresynthesized by reacting an appropriate substituted aminochroman,aminoisochroman, aminothiochroman, aminoisothiochroman,amino-1,2,3,4-tetrahydroquinoline or amino1,2,3,4-tetrahydroisoquinoline with ,B-chloroethylisocyanate in an inertsolvent such as benzene or dioxane to yield a fl-chloroethylurea(Equation A) and dioxane ClOHzCHzN C O or benzene NEIGONHCHzOHzCl QNE-ol 4101 \s O- H:

N-OH:

The urea product of Equation A is usually obtained as an insoluble solidwhich can be isolated by filtration, or if a water miscible solvent suchas dioxane is used in Equation A, water can be added directly to themixture so that reaction B is carried out without isolation of the urea.In Equation B the oxazoline salts are water soluble whereas theby-products are usually insoluble and are removed by filtration.

Precipitation of the product as a solid in Equation C is aided byscratching the inside of the container while adding the ammoniumhydroxide very slowly. r

The oxazoline product is removed by filtration and purified byrecrystallization from an organic solvent system such as acetonitrile,isopropyl alcohol or benzenecyclohexane mixture. If the product is anoil or is water soluble, it is separated from the water by extractionwith a solvent such as methylene chloride. Then the organic solution isdried over magnesium sulfate, filtered and stripped. The residue thusobtained is the desired free base form of the oxazoline which usuallysolidifies upon triturating with a small amount of ethyl ether. If thefree base does not form a solid readily, the solid hydrochloride salt isobtained by gassing an ether solution of the free base.

It is intended to include within the purview of the invention, the acidaddition salts which these compounds form with acids havingpharmaceutically acceptable anions. The term pharmaceutically acceptableanion has a definite meaning to one skilled in the art. It is defined asa non-toxic anion of any of the simple acids commercially used toneutralize basic medicinal agents. These acids include, for example,hydrochloric, hydrobromic, hydroiodic, sulfuric, succinic, maleic,tartaric, citric, glycolic and others. The pharmaceutical activity ofthe molecule is primarily a function of the cation, the anion servingchiefly to supply electric neutrality and water solubility.

v 4 It should be noted that the salts such as the hydrochlo- .ridesdecompose it dry whereas they are stable in solution with water.

By reference to the reaction described above, it can be seen that in theordinary practice of the pharmaceutical process of the invention, theoxazoline salts produced will be hydrobromides, hydrochlorides,hydroiodides, methanesulfonic acid or p-toluenesulfonic acid salts.These salts can be converted to other pharmaceutically acceptable saltsby procedures well known to those skilled in the art. One highly usefulmethod comprises contacting the acid addition salt with a basic anionexchange resin and subsequently adding the prescribed amount of theappropriate acid to the eluant solution containing the free 'base. Forexample, a highly basic compound can be used in this reaction such asthe one available in the trade under the name Amberlite IRA-400. Thisresin is a polyquaternary ammonium compound which is prepared bychloromethylating a highly cross-linked copolymer of styrene anddivinylbenzene followed by treatment of the chloromethylated materialwith a tertiary amine such as trimethylamine.

PHARMACEUTICAL COMPOSITIONS The compounds of this invention hereinaftertermed the active ingredients can be administered alone but aregenerally administered with a pharmaceutically acceptable inert carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice. For example, they can be administered orally indry form, if stabilized, such as in tablets or capsules containing suchexcipients as starch, milk, sugar, certain types of clay, etc. They canbe administered orally in the form of. elixirs or oral suspensions whichcan contain coloring and flavoring agents. They can be injectedparenterally and for this use can be prepared in the form of sterileaqueous solutions containing other solutes such as saline or glucose insufficient quantity to make the solution isotonic. For intramuscularadministration compositions of the compounds of this invention can beprepared in an oil base such as peanut or sesame oil.

The compositions of this invention can take a variety of forms. Variousdiluents can be employed and the percentage of active ingredients can bevaried. It is necessary that an active ingredient form a proportion ofthe composition such that a pharmaceutically effective dosage form willbe obtained. Obviously several dosage unit forms can be administered atabout the same time. Although compositions with less than 0.005% byweight of active ingredients are suitable, it is preferred to usecompositions containing not less than 0.005% of the active ingredient.Otherwise the amount of carrier becomes excessively large. Activityincreases with the concentration of the active ingredient. Thepercentage by weight of the active ingredient can be 10, 50, 75, or evenhigher. Dosage unit forms can be prepared with a major amount of apharmaceutically acceptable inert diluent and a minor proportion ofactive ingredient and vice versa.

Water soluble mixtures containing the compounds of the present inventionare prepared with solid acids such as citric, tartaric,p-toluenesulfonic, maleic, pamoic and succinic acids by uniformly mixingequivalent or molar amounts of the active compounds of this inventionwith the desired acid. These mixtures are stable over extended periodsof time. Aqueous solutions of the desired concentrations can be preparedfrom weighed portions of these mixtures.

DOSAGES The compounds of this invention will be administered in a dosagegenerally of the same or lower order of magnitude as with otherpharmaceutical compounds having similar activity. In some instances theoptimum dosages for compounds of this invention will be lower than theoptimum dosage of other compounds generally recommended for the sameuse.

The expert administering the active ingredient will determine the exactdosage which will be most suitable for a particular application, and asmight be expected, it will vary depending upon the age, weight andgeneral health of the warm-blooded animal under treatment. Oral dosageswill require a larger quantity of the active comadded portionwise.Twenty-five milliliters of ethyl alcohol are added and the mixturerefluxed for 40 minutes. During refluxing all of solid present goes intosolution. The solution is then cooled, filtered and made alkaline by theslow addition of concentrated ammonium hydroxide.

pound than a parenteral dose to produce the same effect Extraction ofthis basic solution with three 50-milliliter in she Warm-blooded anlmaportions of methylene chloride, followed respectively ralt d il g P E Epharmaceutlcally efiectlve by drylng the combined organic phase overmagnesium i f 8 1 p ig E) e actlve cfmlpound 1n the amPunt sulfate,filtratlon and evaporation of solvent, yields 2-(8- 0 kllogrililm of YWelghtthlochromanylamino)-2-oxazoline. f afi consiltutilng aarmaceutlcally Isolation of the urea intermediate in the above synaecvetanfl fun (1)11 comprlszest) e actlve ctl mp0u d 111 the thesis can beavoided by evaporating the ether solution in 2 0 rom 0 Per k1 ogram ofbody Part A containing the free amine, redissolving the amine 2 8 1 th hh in dry dloxane and adding a weighed equivalent of chloroi or Spray P{canon hroug F mouth aI 1d ethyl isocyanate to this solution. The ringclosure (Part nasa pass zlllges constltutllg a p f q i effectlvg B) iscarried out by adding the prescribed amount of amoun W1 compnse a 053g?00 to 25,000 water to the dioxane-urea mixture and proceeding as Ct foran exposure of one minute of actlve compound. above ey q g examples aregwen to A parenteral composition suitable for administration er exemp 1y e mven by injection is prepared by dissolving 5% by weight of EXAMPLE1 2-(8-thlochromanylamino) 2 oxazoline in 95% by volume of physiologicalsaline and sterilizing the result- Y ant solution by filtration. Abuffer can be used if desired. P A h1 h 1 g aminothio Mice are injectedvia the tail vein with the above chroman hydrochloride, 6.4 grams (0.32mole) is added formulation at a dosage of milligram of active to 15milliliters of 20% aqueous sodium hydroxide. The gfedlent P kllogfam 9 yWelght- Maf'ked Central mixture is stirred for fifteen minutes and isextracted BETVQUS System depressloll results exempllfied y twice with 25milliliter portions of ethyl ether. The presslon of spontaneous motoractlvlty and hypothermia combined ether extracts are dried overmagnesium sulfor TOXlcltY Occurs. at Such dosages that fate andfiltered. To the filtrate thus obtained is added a therapeutlc of 50more 15 Obtained- 3.5 grams of 2-chloroethyl isocyanate in 25milliliters of benzene, dropwise, causing an exothermic reaction andEXAMPLES 2 55 the formation of a White precipitate. This precipitate isThe following products are synthesized by combining removed byfiltration and the resultant 1-(2-chloroethyl) the indicatedintermediate amine with 2-chloroethyliso- 3-(8-thiochromanyl)urea isused in Part B. cyanate in the manner described in Example 1 above, PartB. Ring closure to the oxazoline.--Four hundred Parts A and B. Theproduct is formulated and injected in milliliters of water are heated toboiling and 4.5 grams the manner of the 2(8-thiochromanylamino)-2-oxazoof the urea as prepared in the precedingexperiment are line in Example 1. Like results are obtained.

Example No. Intermediate amine Product 5-amino 8 methylthiochroman2-(8-methyl-5-thiochromanylamino)-2-oxaz0line. S-aminoehroman2-(8-ehrolnanylamino)-2-oxazoline. 8-amill0l50thl0chrnmnn2-(8-isothiochromanylamino)-2-oxaz0line. 5-amino-8-methylchroman2-(8-methyl-Erchromanyl-amino) -2-oxazoli.rle. S-aminoisoehrnman2-(S-isochromanylamino)-2-oxazoline. 5-amino-8-methylisothiochroman2-(S-methyl-54sothioehromanylamino)-2-oxazoline. 5 aminoisothioehrnm m2-(5-isothiochromanylamino) -2-oxazoltne. fi-amino-l, 2, 3,4-tetrahydro-1-methylquinoline 2-(1, 2, 3,4-tetrahydro-l-methyl-S-quinolinylamino)-2-oxazoline.framino-B-methoxythiochroman2-(8-methoxy-5-thioehromanylamino)-2-oxazoline.5-amino8-rnethylisoehroman 1 .12-(8-methyl-5-isochromanylamino)-2-oxazoline.

8-amino l, 2, 3, 4-l:etrahydro-l-methylquinoline 2-(1, 2, 3,4-tetrahydro-l-lnethyl-8quinolinylamino)-2-oxazoline. 8-amino-l, 2, 3,4-tetrahydro-2-methyl isoquinoline 2-(1, 2, 3,4-tetrahydro-2-methyl-8isoquinolinylamino)-2-oxazoline.

8-amino S-methylthiochroman 8amino-5, 6-dimethylthiochroman8-amino-2-ethylthiochroman. 8-amino-2,3-diethylthiochroman8-amino-2-propylthiochroman 8-amino-2-butylthiochroman18-amino-6-methylthiochroman. 8-amin0-5,6-dimethylthiochroman5-amino-8-ethylthioehroman 5amino8-isobutylthioehromam 5-amino-8propylchrom an 5-amin0-8-dimethylaminothiochroman5-amino-6,8-dimethylchr0man 5-amino-2,8-dimethylehroman 8arnino-6-methoxychromam 8-amino 5,7-dichlorochroman8-amino-5tluoro-2-methylthiochroman. 8-amino-6-t ert-butylthiochroman.8-amino-6-ehlorochroman 5-arnino-8 methylthiothiochroman. S-amino-8-butylthioisochroman- 5-amino-8-brom0chromam. S-amindS-butoxychromam5-amin0-8-ethoxy-2-methylthiochroman 8-amino-6-isopropylehroman5-amino-2,3,8-trimethylchroman 8-amino2,3,etrimethylchroman5-amino-1,3,8-trimethylisothiochrom 8-amino 1,3,5-trimethylisothiochroman. fi-amino-8 ethylthioisothiochroman-8-amino-5-methylthioisothiochroman 5-amino-8-ethylthiotlllochromam8-amino-5-methylthiothiochrornam 49 S-amino S-dimethylaminothiochromanS-ammo-l,2,3,4-tetrahydro-1,2-dimethylquinolineI 5-amino-2,B-dimethyl-l, 2, 3, itetrahydroisoquinollne. 2-(1, 2, 3,

2-(5-methyl-8-thiochromanylamino)-2-oxazoline.

4-tetrahydro-2, 8-dimethyl-5-isoquinolinylamino)-2-oxazoline 2-(5,fi-dimethyl-S-thiochromanylamino)-2-oxazoline.

2-(2-methyl-8-thioehromanylamino)-2-oxazoline.2-(2,3-diethyl-8tlochromanylanlino)-2-oxazoline.2-(2-propyl-8-thiochromanylamino)-2-0xazoline.

2-(2-butyl-8-thioehromanylamino)-2-oxazoline.

2-(6-methyl-8-thiochromanylamino)-2-oxazoline.2-(5,fi-dimethyl-S-thiochromanylamiuo)-2-oxazoline.2-(8-ethyl-5-thioehromanylamino)-2-0xazoline.

2-(8-isobutyl-5-thlochromanylamino)-2-oxazollne.

2-(8-propy1-5 chromanylamino)-2-oxazoline.

2-(S-dimethylamino)-5-thiochromanylamino)-2-oxazoline.2-(6,8-dimethyl-5-chromanylamino)-2-oxazoline.

2-(2,8-dimethyl-5-chromanylamino)-2-oxazoline.

2-(ti-methoxy-8-chromanylamino)-2-0xazoline.

2- (5, 7-dichloro-8-ehromanylamino) -2-oxazoline.

2-(5 fluoro-2-methyl-8-thiochromanylamino)-2-oxazoline.2-(6-tert-butyl-8-thioehromanylamino)-2-oxazoline.

2-(6-chloro-8-chromanylamino)-2-oxaz0line.

2-(1,2,3,4-tetrahydro-1,2-dimethyl-S-quinolinylamino)-2-oxazoline. 2-(8methylthio-5-thiochromanylamin0)-2-0xazoline.

2-(8-bromo-5-chromanylamino)-2-oxazoline.

2-(S-butoxy-5-chromanylamino)-2-oxazoline.2-(8-eth0xy-2-rnethyl-5-thiochromanylamino)-2-oxaz0line.2-(6-isopropyl-8-chromanylamino)-2-oxazoline.2-(2,3,8-trimethyl-S-chromanylamino)2-oxazoline.2-(2,3,5-trimethyl-8-chromanylamino)-2-oxazoline.

2-(1,3,E-trirnethyl-5-isothioehromanylamino)-2-oxazoline.2-(1,3,5-trimethyl-B-isothiochromanylamino)-2-oxazol1ne.

. 2-(8-ethylthio-fi-isothiochromanylamino)-2-oxazoline.

. 2-(5-methylthio-8-isothioehromanylamirio)-2-oxazo1ine.2-(S-ethylthio-fi-thiochromanylamino)-2-oxazoline.

2- (5-methylthio-8-thiochromanylarnino) -2-oxazoline.

2- (5-dimethylamino-8-thioehr0manylamlno) -2-oxazollne.

Example No. Intermediate amine Product 50S-amino--dimethylaminoisothiochromarn2-(5-dimethylamino-8-isothioehromanylamlno)-2-oxazoline.

"I: 8-amino-2,3,7,8-tetramethylthiochroman 8-amino-1,3,7,S-tetramethylisothioehroman2-(B-dimethylamino-5-isothiochromanylamino)-2-oxazoline.

2-(2,3,6,8-tetramethyl-5-thi0chromanylamino)-2-oxazoline.

2-(1,3,7,S-tetrarnethyl-S-thiochromanylamino)-2-oxazoline.

2-(2,3,7,8-tetramethyl-8-thiochromanylamino)-2-oxazoline.

-(1,3,7,$-tetramethyl-8-isothiochromanylamino)-2-oxazoline.

EXAMPLE 56 A large number of unit capsules are prepared for oraladministration by mixing the following ingredients:

Parts by weight 2-(8-thioehromanylamino) 2 oxazoline 2,000

Lactose U.S.P. 7,950 Dry pyrogenic silica SiO with particle size of0.015 micron, surface area of 200 mf /gm and bulk density of 2.2 lbs/cu.ft. (Cabosil," Cabot Corp.) 50

After mixing, the mixture is screened through a 40 mesh screen andencapsulated in No. 3 two-piece hard gelatin capsules.

EXAMPLE 57 2-(8-thiochromanylamino)-2-oxazoline (20 parts by weight) isdispersed in 100 parts by volume of corn oil and encapsulated to formstandard soft gelatin capsules.

EXAMPLE 58 Tablets for oral administration are prepared by mixing 50milligrams of 2-(8-thiochromanylamino)-2-oxazoline, 2.5 milligrams ofgelatin, 2.5 milligrams of magnesium stearate and 100 milligrams ofstarch, and forming the mixture into tablets by a conventional tabletingmachine. Slow release pills and tablets can also be used.

EXAMPLE 59 EXAMPLE 60 Mongolian gerbils are placed in a l6-litersemi-dynamic exposure chamber into which2-(1,2,3,4-tetrahydro-lmethyl-'S-quinolinylamino)-2-oxazoline,formulated in the same manner as the active ingredient of Example 59, isaerosolized so that the animals are exposed to 3000 Ct for one minute.The gerbils exhibit marked decreased locomotor activity for about onehour after treatment.

EXAMPLE 61 Mice are placed in a 2.85-liter bell-jar chamber into whichan acetone solution of Z-(S-methoxy-S-chromanylamino) -2-oxazoline isaerosolized so that the animals are exposed to a nominal 8000 Ct of thecompound for two minutes. Pronounced central nervous system depressionoccurs as shown by a decrease in spontaneous locomotor activity by themice as measured in a Woodard Activity Cage Counter 20 minutes afterexposure. Recovery is normal and no toxicity occurs at C! values 10times greater than that used.

EXAMPLE 62 Beagle dogs are injected via the cephalic vein with asterilized suspension containing 1% by weightZ-(S-chromanyl)-2-oxazoline and 99% by volume of a vehicle consisting of10% acetone and 90% of 0.5% methyl cellulose in water. The dosage ofactive ingredient is 0.032

milligram per kilogram of body weight. Central nervous system depressionresults as shown by sedation, ataxia and depression. Recovery of normalfunction occurs in about two hours.

EXAMPLE 63 Cats are given intravenous administration of the 2-(8-methyl-S-thiochromanylamino)-2-oxaoline, 0.05 I milligram per kilogram,formulated in a serilized solution containing 1% by weight of the activeingredient and 99% by volume of a vehicle consisting of 10% acetone andmethylcellulose in Water. Central nervous system depression resultspromptly as shown by decreased locomotor activity, ataxia, anddifliculty in maintenance of righting reflex. Recovery without injuriousafter effects occurs in a few hours.

EXAMPLE 64 A male rhesus monkey is given via the femoral vein aninjection of a sterilized solution containing 5% by Weight2-(S-isothiochromanyl)-2-oxazoline hydrochloride and by volume ofphysiological saline. The active ingredient is given at a dosage of 0.1milligram per kilogram of body weight. Central nervous system depressionoccurs as evidenced by loss of aggressive behavior and the animalbecomes briefly prostrated. Toxicity occurs at such doses that atherapeutic ratioof 10 or more is obtained.

EXAMPLE 6 5 Rats are treated intramuscularly with a sterilizedsuspension containing 5% by weight2-(3-methyl-8-thiochromanylamino)-2-oxazoline and 95% by volume ofphysiological saline. The active ingredient is given at a dosage of 0.2milligram per kilogram of body weight. In 10 minutes central nervoussystem depression results, as exemplified by ataxia and decrease inspontaneous motor activity. Toxicity occurs at such doses that atherapeutic ratio of or more is obtained.

EXAMPLE 66 A sterilized suspension containing 5% by weight 2-(3-methyl-8-thiochromanylamino)-2-oxazoline and 95% by volume ofphysiological saline is intraperitoneally administered to mice. Theactive ingredient is given at a. dosage of 1 milligram per kilogram ofbody weight. It produces central nervous system depression exemplifiedby decreased locomotor activity and decreased rearing and snifliing.Toxicity occurs at such doses that a therapeutic ratio of 30 or more isobtained.

EXAMPLE 67 A sterilized suspension containing 5% by weight of2-(S-ethyl-S-thiochromanylamino-)-2-oxazoline and 95% by volume ofphysiological saline. The active ingredient is administeredsubcutaneously to rats at a dosage of four milligrams per kilogram ofbody Weight. Central nervous system depression characterized by abnormalgait and decreased spontaneous activity results. Toxicity occurs at suchdoses that a therapeutic ratio of 20 or more is obtained.

EXAMPLE 68 A sterilized suspension containing 5% by weight of2-(S-ethoxy-S-chromanylamino) -2-oxazoline and 9'5 by volume of peanutoil is administered todogs. The active ingredient is given orally at adosage of one milligram per kilogram. of body weight. Marked sedationfor several hours followed by normal recovery is observed.

Compounds of my invention can be combined with anticholinergics as setforth in an application assigned to my assignee, Ser. No. 348,291 filedFeb. 28, 1964. The mixtures obtained also exhibit central nervous systemdepressant activity. The oxazolines of this invention can be combinedwith the anticholinergics of the aforementioned application at likerates and can be applied to animals in like manner. The disclosure ofSer. No. 348,291 is herein incorporated by reference.

Whereas the above examples describe effects on lower order warrn-bloodedanimals, the invention is not limited to use in just these animals. Itis believed that the compounds herein described are also useful ascentral nervous system depressants in higher order animals includinghumans.

What is claimed is:

1. A compound of the formula:

wherein X is selected from the group consisting of oxygen and sulfur;

R is selected from the group consisting of hydrogen and methyl;

R is selected from the group consisting of hydrogen, alkyl of 1 through4 carbon atoms, and alkoxy of 1 through 4 carbon atoms;

R" is selected from the group consisting of hydrogen and methyl; and

R' is selected from the group consisting of hydrogen and methyl. 2. Acompound of the formula:

wherein X is selected from the group consisting of oxygen and sulfur;

R is selected from the group consisting of hydrogen, alkyl of 1 through4 carbon atoms and alkoxy of 1 through 4 carbon atoms.

3. A compound according to claim 2 which is 2-(8- thiochromanylamino-2-oxazoline.

4. A compound according to claim 2 which is 2-(8-methyl-S-thiochromanylamino -2-oxazoiine.

5. A compound according to claim 2 which is 2-(8- chromanylamino-2-oxazoline.

6. A compound according to claim 2 which is 2-(8- isotliiochromanylamino-2-oxazoline.

7. A compound according to claim 2 which is 2-(8-methyl-5-chromanylamino)-2-oxazoline.

8. A compound according to claim 2 which is 2-(8-isochromanylamino)-2-oxazoline.

9. A compound according to claim 2 which is 2-(8methyl-5-isothiochromanylamino -2-oxazoline.

10. A compound according to claim 2 which is 2-(5- thiochromanylamino)-2-oxazoline.

11. A compound according to claim 2 which is 2-(8-methoxy-5-thiochromanylamino)2-oxazoline.

References Cited UNITED STATES PATENTS 2,493,748 1/ 1950 Brooker et al260-288 X 2,870,159 1/1959 Bloom 260-307 2,870,160 1/1959 Bloom 260-3072,870,161 1/1959 Bloom 260-307 2,876,223 3/1959 Bloom 260-288 X2,889,351 6/ 1959 Bloom 260-307 2,992,232 11/1961 Bloom 260-307 X3,278,382 10/1966 Poos 260-307 3,340,266 9/1967 Howe et al 260-288DONALD G. DAUS, Primary Examiner US. Cl. X.R. 260-286, 288, 327, 345.5,453, 553; 424-258, 272

